My goal, using this Mentored Clinical Scientist Career Development Award, is to achieve expertise in Molecular Oncology so that I may become an independent investigator in Breast Cancer Research. I have had a long- standing commitment to translational, patient-oriented research and treatment in the field of medical oncology, as evidenced by my clinical and research training. My career focus is the translation of basic science concepts into practical improvements for patients being treated for breast cancer (BC). I am particularly interested in developing innovative treatments for patients with triple negative breast cancer (TNBC) by understanding both the biology and etiology of this disease. Unlike the targeted therapies identified by basic science to successfully treat hormone receptor (ER+/PR+) and growth factor (HER2+) overexpressing breast cancer, I have been frustrated by the lack of rational therapies for TNBC and as a result have witnessed the difficulty in successfully treating patients with TNBC. It is because of the inability to effectively treat TNBC that I have performed research for the past 2.5 years working with Dr. K. Frenkel, investigating the diverse anti-tumor effects of caffeic acid phenethyl ester (CAPE). CAPE is a major bioactive component of propolis, a natural product gathered by honeybees and used safely for millennia. My published work has shown that CAPE inhibits breast cancer cells, including MDA-MB-231 (MDA-231, a model for TNBC) breast tumor growth in vitro as well as in vivo via cell cycle arrest, apoptosis and inhibition of angiogenesis (Jing W, Omene C, 2011). Importantly, CAPE inhibits MDA-231 TNBC stem cells with a subsequent decrease in tumor-forming potential (Omene C, 2011). We found through the collaboration with Dr. OA O'Connor that these anti-tumor effects of CAPE are related in part to its role as a histone deacetylase (HDAC) inhibitor (Omene C et al, unpublished). For example, CAPE exposure leads to a decrease in EGFR over-expression, a key driver in the proliferation of TNBC, and epigenetically, causes the re-expression of a previously silenced estrogen receptor (ER) gene in MDA- 231 TNBC cells. This project offers me a unique opportunity to study the development of TNBC and attempt to modify the risk of its development by CAPE, using a new mouse model of TNBC established by Dr. Barcellos-Hoff, my mentor for this award. This radiation chimera model in which an irradiated host is transplanted with oncogenic Trp53 null mammary epithelium exhibits an accelerated development of aggressive tumors whose molecular signatures are distinct from tumors arising in non-irradiated hosts. Tumors arising in the irradiated host are predominantly estrogen receptor negative and this was linked to mammary stem cell (MaSC) deregulation. This model will allow me to meld together data from my work using CAPE and interest in TNBC to test whether CAPE can be used to modify the risk of developing TNBC. We hypothesize that prevention of cancer development in this TNBC model will be achieved by CAPE due to its novel HDAC inhibitor properties. We plan to: 1) Establish whether CAPE affects tumor latency and/or tumor type in irradiated mice, 2) Determine whether CAPE modifies the mammary stem cell pool isolated from irradiated mice and 3) Assess the effect of CAPE action as an inhibitor of histone deacetylase in irradiated cells. This research will significantly contribute to our understanding of TNBC development. It has the potential to be readily translatable as chemoprevention in the clinical setting for populations at high risk for TNBC. In addition, TNBC patients have limited treatment options and CAPE used as chemoprevention could impact on the prognosis of these women. I am confident that I can accomplish the goals as outlined in this proposal as I move toward becoming an independent investigator given the wide array of resources available to me. They include an outstanding researcher as a mentor, a multitude of educational opportunities, an excellent institutional environment, shared core facilities and many expert key faculty members readily available to share their expertise. ! PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE it is well known that triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high mortality and especially high prevalence in African American women. Therefore, there is a pressing need to understand the biology of this disease and to develop new agents that would increase survival of these patients. This research provides for the first time, a unique TNBC model, by which we can explore and potentially modify the risk of developing TNBC using CAPE, the active component in propolis, a safe natural product with anti-tumor effects in breast cancer that can be easily translated into the clinical setting. !